title: URI is an oncogene amplified in ovarian cancer cells and is required for their survival.
abstract: Abrogation of negative feedback control represents a fundamental requirement for aberrantly activated signaling pathways to promote malignant transformation and resistance to therapy. Here we identify URI, which encodes a mitochondrial inhibitor of PP1γ and PP1γ-mediated feedback inhibition of S6K1-BAD survival signaling, as an oncogene amplified and overexpressed in ovarian cancer cell lines and human ovarian carcinomas. URI is an "addicting" oncogene selectively required for the survival of ovarian cancer cells with increased URI copy number. By constitutively detaining PP1γ in inactive complexes, URI sustains S6K1 survival signaling under growth factor-limiting conditions and mediates resistance of cells to cisplatin. Thus, oncogenic activation of URI defines an important mechanism for activating mitochondrial S6K1-BAD signaling and promoting cell survival through disabling PP1γ-dependent negative feedback inhibition.
authors.affiliation: Institute of Cell Biology, ETH Zurich, 8093 Zurich, Switzerland.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Theurillat
authors.forename: Stefan Christian
authors.initials: SC
authors.lastname: Metzler
authors.forename: Nico
authors.initials: N
authors.lastname: Henzi
authors.forename: Nabil
authors.initials: N
authors.lastname: Djouder
authors.forename: Marianne
authors.initials: M
authors.lastname: Helbling
authors.forename: Anna-Kathrin
authors.initials: AK
authors.lastname: Zimmermann
authors.forename: Francis
authors.initials: F
authors.lastname: Jacob
authors.forename: Alex
authors.initials: A
authors.lastname: Soltermann
authors.forename: Rosmarie
authors.initials: R
authors.lastname: Caduff
authors.forename: Viola
authors.initials: V
authors.lastname: Heinzelmann-Schwarz
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.forename: Wilhelm
authors.initials: W
authors.lastname: Krek
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D054645:Protein Phosphatase 1 / Q000378:metabolism; D034622:RNA Interference; D012097:Repressor Proteins; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000235:genetics; D051025:bcl-Associated Death Protein / Q000378:metabolism
chemical_list: C494819:BAD protein, human; D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D012097:Repressor Proteins; C117184:URI1 protein, human; D051025:bcl-Associated Death Protein; D019893:Ribosomal Protein S6 Kinases; D054645:Protein Phosphatase 1